Hodgkin Lymphoma—The Effect of Chemotherapy on Gonadal Function and Fertility Is Strongly Related to the Treatment Regimen, Age, and Sex: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study is one of the first large-scale meta-analyses within the FertiTOX project to quantify infertility risk in Hodgkin lymphoma (HL) survivors according to chemotherapy regimen, sex, and age. It synthesizes data from 50 studies, of which 43 were included in the meta-analysis, encompassing 5564 female and 1631 male survivors—substantially larger than most previous single-center or cohort investigations. The findings show that BEACOPP is associated with the highest infertility risk (approximately 38% in women and 81% in men), whereas ABVD carries the lowest risk (around 6% in both sexes). These results confirm earlier observations from smaller studies but provide more precise estimates. Overall, men exhibited a higher prevalence of infertility (45%) than women (21%). Age-specific analyses revealed that adolescent females had a relatively low risk (8%), while adolescent males remained highly vulnerable (67%), an important nuance that had not been clearly established before.

Clinically, the authors recommend individualized fertility counseling. For patients treated with ABVD and for adolescent females, post-treatment fertility monitoring is advised. In contrast, fertility preservation prior to therapy is strongly recommended for BEACOPP-treated patients and for males in general.

Several terminology and stylistic considerations could strengthen the manuscript. Using a single, consistently defined term for gonadal damage—such as “presumed infertility” or “suspected infertility”—would improve clarity. Harmonizing age-related terminology (e.g., “children/adolescents,” “pediatric,” “younger patients”) would also enhance readability. Certain phrases could be tightened; for example, instead of stating that “chemotherapy was assumed,” it may be clearer to specify that patients were reported as treated for HL during eras when chemotherapy-based regimens were standard, although individual regimen details were not always available.

The manuscript appropriately acknowledges key limitations, including the predominance of observational and retrospective data, reliance on surrogate markers rather than live birth outcomes, limited and sometimes poorly characterized pediatric cohorts, and uncertainty regarding pubertal status. Given the substantial heterogeneity reported in the results, explicitly linking this heterogeneity to caution in interpreting pooled prevalence—particularly in adult and mixed-regimen groups—would further strengthen the discussion. Differences in cumulative doses, supportive care, follow-up duration, and outcome definitions likely contribute to this variability. Additionally, the definition of “presumed infertility” varies across studies (e.g., hormonal, menstrual, or semen-based endpoints), which may introduce misclassification and lead to under- or overestimation of clinically meaningful infertility.

Ensuring consistent terminology throughout—avoiding shifts between “presumed infertility,” “infertility,” and “gonadal impairment”—would reduce ambiguity, especially if “presumed infertility” is clearly defined early as a surrogate-marker–based construct. A few long sentences, particularly those listing multiple regimens (MOPP, COPP, OPPA, etc.) or explaining BrECADD, could be shortened or divided for clarity. Minor language refinements include using “better-tolerated” instead of “beĴer-tolerated,” standardizing capitalization of regimen names, and applying uniform rounding conventions for percentages.

Author Response

1) Reviewer comment: Given the substantial heterogeneity reported in the results, explicitly linking this heterogeneity to caution in interpreting pooled prevalence would further strengthen the discussion.

2) Response: We thank the reviewer for this important suggestion. We have expanded the Discussion to more explicitly address the high degree of heterogeneity observed across pooled estimates, particularly in adult and mixed-regimen analyses. We now emphasize that pooled prevalence estimates of presumed infertility should be interpreted with caution and discuss likely sources of heterogeneity, including differences in cumulative chemotherapy exposure, supportive care, follow-up duration, and outcome definitions.

2) Reviewer comment: Ensuring consistent terminology throughout—avoiding shifts between “presumed infertility,” “infertility,” and “gonadal impairment”—would reduce ambiguity.

2) Response: We agree and have revised the manuscript to consistently use the term “presumed infertility” throughout. This term is now clearly defined early in the manuscript as a surrogate-marker–based construct rather than a live birth outcome, and alternative terms have been removed to improve clarity and consistency.

3) Reviewer comment: The definition of presumed infertility varies across studies and may introduce misclassification.

3) Response: We have addressed this point by expanding the Limitations section to explicitly acknowledge the heterogeneity of definitions used for presumed infertility across studies, including hormonal, menstrual, and semen-based endpoints. We now discuss how this variability may contribute to misclassification and potential under- or overestimation of clinically meaningful infertility.

4) Reviewer comment: Certain phrases (e.g., “chemotherapy was assumed”) could be clarified.

4) Response: We have clarified in the manuscript that patients were treated for Hodgkin lymphoma during periods in which chemotherapy-based regimens were standard of care. Individual regimen details were not always reported, particularly in older studies; nevertheless, the assumption of systemic treatment exposure remains valid, and we have explicitly acknowledged this limitation in the revised Limitations section.

5) Reviewer comment: Several terminology and stylistic considerations could strengthen the manuscript.

5) Response: We have revised the manuscript to address these points. Age-related terminology has been harmonized throughout, consistently using “children/adolescents” instead of “pediatric” or other variants. Long sentences, particularly those listing multiple chemotherapy regimens, have been shortened or split for improved readability. Minor language and formatting issues, including spelling, capitalization of regimen names, and percentage rounding, have also been corrected to enhance clarity and consistency.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a systematic review of the literature on the impact of chemotherapy on gonadal function and fertility in Hodgkin lymphoma.  The topic is timely, clinically relevant, and remains relatively underexplored in the existing literature, which underscores the value of such a review. The work is extensive and includes a detailed analysis of the available studies.

Strengths of the Manuscript
• High clinical and scientific relevance of the topic

• Strict adherence to PRISMA
  • Thorough and comprehensive discussion
• Clarity in describing fertility preservation strategies

Author Response

Reviewer comment: The manuscript presents a systematic review of the literature on the impact of chemotherapy on gonadal function and fertility in Hodgkin lymphoma. The topic is timely, clinically relevant, and remains relatively underexplored. The work is extensive and includes a detailed analysis of the available studies. Strengths include high clinical relevance, strict adherence to PRISMA, a thorough discussion, and clarity in describing fertility preservation strategies.

Response: We thank the reviewer for this positive and encouraging assessment of our work. We are pleased that the clinical relevance, methodological rigor, adherence to PRISMA guidelines, and clarity of the discussion—particularly regarding fertility preservation strategies—were recognized. No changes were required in response to this comment.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript. This paper addresses infertility among patients with Hodgkin lymphoma treated with ABVD or BEACOPP, and your findings that the risk of infertility is approximately 6% after ABVD and 40% in women and 80% in men after BEACOPP are valuable and clinically relevant. I have only one main question.

You stated that studies including women with a median or mean age of 30 years or older at the time of diagnosis or treatment were excluded. However, it appears that some of the included studies still contained patients aged 30 years or older. Could you please clarify how these patients were excluded in practice? Additionally, please explain the rationale for excluding women aged 30 years or older, as this justification is currently unclear in the manuscript.

Author Response

Reviewer comment: You stated that studies including women with a median or mean age of 30 years or older were excluded. However, some included studies appear to contain patients aged 30 years or older. Please clarify how these patients were excluded in practice and explain the rationale for excluding women aged 30 years or older.

Response: We thank the reviewer for highlighting this important point and for the opportunity to clarify our methodology. The age criterion was applied at the study level rather than the individual patient level. Specifically, studies were excluded if the reported mean or median age of female participants at diagnosis or treatment was 30 years or older. Studies with mean or median ages below this threshold were included even if they contained a proportion of individual patients aged 30 years or older, as individual-level exclusion was not possible using aggregated published data.

The rationale for selecting an age threshold of 30 years was to reduce confounding by age-related decline in ovarian reserve, which becomes increasingly relevant from the early thirties onward and may independently influence fertility outcomes. This approach was intended to better isolate chemotherapy-associated gonadotoxic effects.

We have clarified both the practical application and the rationale for this criterion in the revised manuscript.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The author’s have addressed reveiwer's comments.